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Objective We evaluated the diagnostic accuracy of computed tomography (CT)-guided transthoracic core needle biopsy (TCNB) for small (≤20-mm) lung nodules and identified predictive factors for true negatives among benign biopsy results. Methods From March 2010 to June 2015, 222 patients with small lung nodules underwent CT-guided TCNB. We retrospectively analysed data regarding technical success, diagnostic accuracy, and predictors of true negatives. Results The technical success rate was 100%. The TCNB results of the 222 lung nodules included malignancy (n = 136), suspected malignancy (n = 8), specific benign lesion (n = 17), and nonspecific benign lesion (n = 61). The final diagnosis of 222 lung nodules included malignant (n = 160), benign (n = 60), and nondiagnostic lesions (n = 2). The sensitivity, specificity, and overall diagnostic accuracy of CT-guided TCNB for small lung nodules were 90.0%, 100%, and 92.7%, respectively. Pneumothorax and haemoptysis occurred in 23 and 41 patients, respectively. Based on the Cox regression analysis, the significant independent predictive factor for true negatives was a biopsy result of chronic inflammation with fibroplasia. Conclusions CT-guided TCNB offers high diagnostic accuracy for small lung nodules, and a biopsy result of chronic inflammation with fibroplasia can predict a true-negative result.